Dent Disease in Chinese Children and Findings from Heterozygous Mothers: Phenotypic Heterogeneity, Fetal Growth, and 10 Novel Mutations

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• 作者：Fucheng Li ; BSc¹ ; Zhihui Yue ; MD ; PhD² ; Tingting Xu ; MSc³ ; Minghui Chen ; MD ; PhD⁴ ; Liangying Zhong ; MD⁵ ; Ting Liu ; MD² ; Xiangyi Jing ; MD⁶ ; Jia Deng ; MSc⁷ ; Bin Hu ; BSc¹ ; Yuling Liu ; MD⁸ ; Haiyan Wang ; MD⁹ ; Kar N. Lai ; MD ; PhD¹⁰ ; Liangzhong Sun ; MD ; PhD² ; Jinsong Liu ; PhD³ ; Patrick H. Maxwell ; MB BS ; DPhil¹¹ ; Yiming Wang ; MD ; PhD¹² ; ¹³ ; ^{ywzhong@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：diagnosis ; nephrocalcinosis ; nephrolithiasis ; mutations ; structural modeling
• 刊名：The Journal of Pediatrics
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：174
• 期：Complete
• 页码：204-210.e1
• 全文大小：1021 K

文摘

To characterize the phenotypes of Dent disease in Chinese children and their heterozygous mothers and to establish genetic diagnoses.

Study design

Using a modified protocol, we screened 1288 individuals with proteinuria. A diagnosis of Dent disease was established in 19 boys from 16 families by the presence of loss of function/deleterious mutations in CLCN5 or OCRL1. We also analyzed 16 available patients' mothers and examined their pregnancy records.

Results

We detected 14 loss of function/deleterious mutations of CLCN5 in 15 boys and 2 mutations of OCRL1 in 4 boys. Of the patients, 16 of 19 had been wrongly diagnosed with other diseases and 11 of 19 had incorrect or unnecessary treatment. None of the patients, but 6 of 14 mothers, had nephrocalcinosis or nephrolithiasis at diagnosis. Of the patients, 8 of 14 with Dent disease 1 were large for gestational age (>90th percentile); 8 of 15 (53.3%) had rickets. We also present predicted structural changes for 4 mutant proteins.

Conclusions

Pediatric Dent disease often is misdiagnosed; genetic testing achieves a correct diagnosis. Nephrocalcinosis or nephrolithiasis may not be sensitive diagnostic criteria. We identified 10 novel mutations in CLCN5 and OCRL1. The possibility that altered CLCN5 function could affect fetal growth and a possible link between a high rate of rickets and low calcium intake are discussed.